Amyloid beta peptide (Abeta) immunization has emerged as a novel therapeutic strategy for the treatment or prevention of Alzheimer's Disease (AD). In AD mouse models, the efficacy of this approach appears to be dependent on the ability to achieve a high level of anti-Abeta antibody (Ab) in response to immunization with Abeta or to deliver a large quantity of certain anti-Abeta Abs by passive immunization. Based on these data, Abeta immunotherapy is being pursued as a potential therapeutic strategy for AD. The recent phase II trial of direct Abeta42 immunization was halted due to an apparent meningio-encephalitic like presentation in -5% of individuals. These side effects have raised serious concerns about the continued clinical development of anti-Abeta immunization, and have galvanized the field to focus on potential inflammatory and autoimmune consequences of Abeta immunotherapy. Despite the setback in the phase II trial, it is our opinion that Abeta immunization or derivative approaches are still worthy of further investigation. However, the success and tolerability of future studies may well depend on the mechanism or mechanisms through which Abeta immunization works. During the previous funding period, a major focus of our work was to determine whether enhanced microglial uptake of Abeta:anti-Abeta complexes via FcR contributed to the efficacy of immunization. These studies, performed in Tg2576 mice in a FcRgamma-/- background, demonstrate that FcR mediated uptake of antibodies by microglia does not appear to play a role in the outcome of either a therapeutic or preventative Abeta immunization study in Tg2576 mice. Such studies suggest that any molecule with Abeta binding properties similar to the anti-Abeta produced upon Abeta immunization may be all that is needed for therapeutic efficacy. If this is the case, then it is possible that derivative strategies targeting Abeta with high affinity binding agents can avoid immune related side effects. The proposed studies aim to further explore the potential mechanism by which immunization works and the possible limitations of the immunization approach.